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“ “ Cardiac Resynchronization Cardiac Resynchronization Therapy ”Therapy ”

Stefano Nardi, MD

AZIENDA OSPEDALIERA SANTA MARIA TERNIAZIENDA OSPEDALIERA SANTA MARIA TERNIDIPARTIMENTO CARDIOTORACOVASCOLAREDIPARTIMENTO CARDIOTORACOVASCOLARE STRUTTURA COMPLESSA DI CARDIOLOGIA STRUTTURA COMPLESSA DI CARDIOLOGIA

UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE

NYHA CLASS

Annual su

rviv

al (%

)

Hosp

italiz

ati

ons

/ year

100

75

50

25

0

I II III IV

1

10Survival

Hospitalization

.1

Hospitalization / NYHA-class

Cardiac Resynchronization Cardiac Resynchronization TherapyTherapy

Quality of Life for HF patients Overall perception of health

36

45

55

48

48

52

56

58

70

Heart Failure NYHA Class I V

Heart Failure NYHA Class I I I

Heart Failure NYHA Class I I

Chronic Bronchitis

Valve disease symptomatic

AF symptomatic

Angina

Depression

General population

Hobbs FDR, et al. Eur Heart J 2002


Sinusnode

AVnode

Bundlebranch or

diffuse block

Delayed conduction

•Delayed AV

sequence

•Mitral regurgitation

•Decreased filling

time

Delayed Ventricular Delayed Ventricular ActivationActivation

What is abnormal in the HF What is abnormal in the HF pts?pts?


SinusSinusnodenode

AVAVnodenode

BundleBundlebranch orbranch or

diffuse blockdiffuse block

Delayed conductionDelayed conduction

• Abnormal RV-LV sequence

• Abnormal LV activation sequence

• Segmentary dyskinesia

• Aggravation of mitral regurgitation

• Disynchrony of RV and LV filling flowsDyssynchrony Ventricular Dyssynchrony Ventricular

ContractionContraction

What is abnormal in the HF What is abnormal in the HF pts?pts?


• Reduced LVEF remains the single most important risk factor for overall mortality and SCD.1

• Increased risk is measurable at EF above 30%, but an EF ≤30% is the single most powerful independent predictor for SCD.2

1Prior SG, Aliot E, Blonstrom-Lundqvist C, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J, Vol. 22; 16; August 2001.

2 Myerburg RJ, Castellanos A. Cardiac Arrest and Sudden Cardiac Death, in Braunwald E, Zipes DP, Libby P, Heart Disease, A textbook of Cardiovascular Medicine. 6th ed. 2001. W.B. Saunders, Co., p. 895.

Relationship of SCD Relationship of SCD and LV Dysfunctionand LV Dysfunction


Which is the prognostic value of QRS width ?• VEST study analysis

• NYHA Class II – IV pz

• 3,654 ECGs digitally scanned

• Age, creatinine, LVEF, heart rate, and QRS duration found to be independent predictors of mortality

• Relative risk of widest QRS group 5x greater than narrowest

60%

70%

80%

90%

100%

0 60 120 180 240 300 360Days in Trial

Cu

mu

lati

ve S

urv

ival

QRS Duration (msec)

<9090-120

120-170170-220

>220

Adapted from Gottipaty et al. JACC 1999; 33(2):145A (abstract 847-4)


CHF Population

6.5 Mio

NYHA III + IV (30 - 35%)

1.95 Mio

Wide QRS (10 - 30%)

Resynchronization Rx Target Population:195’000

650’000

Incidence = 580’000 (9.0%)Mortality = 300’000 (4.6%)

CHF Population in CHF Population in EuropeEurope


•WHO? Which criteria ?

•WHEN? Which NYHA class ?

•WHERE? RV+LV / LV ?

•WHY? Symptoms / Mortality ?

KEY QUESTIONSKEY QUESTIONS


• Optimizes AV contraction sequence

• Reduces pre-systolic mitral regurgitation

• Improves atrial preloading of the ventricle

• Increases filling time

Mechanism IMechanism IAtrio-Ventricular SynchronyAtrio-Ventricular Synchrony

Cardiac Resynchronization Cardiac Resynchronization TherapyTherapyWhat does pacing What does pacing changechange??

OAVD Restores AV Synchrony

PP RR

INTRINSICINTRINSIC

AorticAorticpressurepressure

LVLVpressurepressure

PPPP

PeakPeakatrial systoleatrial systole

Start ofStart ofLV systoleLV systole

DiastolicMitral

Regurgitation

MaximumEffective Preload

PP VV

PACEDPACEDPPPP

SynchronizedSynchronizedLV and atrialLV and atrial

systolessystoles

Auricchio et al, PACE 1998


• Optimizes ventricular activation

• Increases pumping effectiveness

• Reduces regional wall stress (WMSI)

• Decreases mitral regurgitation

• Resynchronizes ventricular filling flows

• Decreases filling pressures


Mechanism IIMechanism IIVentricular CoordinationVentricular Coordination

What does pacing What does pacing changechange??

LV Lead Implant Historical Evolution

• Thoracic epicardial LV lead - 1994 1

• RV lead adapted for transvenous LV implant - 1996 2

• CS lead adapted for transvenous LV implant -1997 3

• Special designed transvenous LV lead - 1998 4

• Guiding catheter sheath for LV lead delivery -1998 5

1. Bakker et al. PACE 1994; 2. Cazeau et al. PACE 1996; 3.Daubert et al. PACE 1997; 4. Gras et al. PACE 1998 5. Lurie et al. Circulation 1998


Blanc et al., Circulation 199723 pts mean SD

90

100

110

120

130

140

150

SYSTOLIC SYSTOLIC Blood PressureBlood Pressure

RVARVA LV BVRVORVOBASBAS

mm

Hg

mm

Hg

p<.01p<.03

0

10

20

30

40

Pulmonary Capillary Pulmonary Capillary Wedge PressureWedge Pressure

RVARVA LV BVBVRVORVOBASBAS

p<.01p<.01

Acute studies


Kass et al, Kass et al, Circulation 99Circulation 99

IntrinsicIntrinsicPacedPaced

00 100100 200200 30030000

4040

8080

120120

RV SeptumRV Septum

00 100100 200200 30030000

4040

8080

120120BiventricularBiventricular

00 100100 200200 30030000

4040

8080

120120

RV ApexRV Apex

00 100100 200200 30030000

4040

8080

120120LV FreewallLV Freewall

LV Volume LV Volume (mL)(mL)

LV P

ress

ure

LV P

ress

ure

(m

m H

g)

(mm

Hg

)LV

Pre

ssu

reLV

Pre

ssu

re

(mm

Hg

)(m

m H

g)

LV Volume LV Volume (mL)(mL)

Acute studies


Auricchio et al., NASPE ‘99

PATH-CHF: Inclusion Criteria (42 pts)

• Dilated cardiomyopathy of any etiology• NYHA Class III (> 6 months) or NYHA IV• Optimal individual drug therapy • QRS duration >120 msec • PR Interval >150 msec• Sinus rate > 55 bpm• No conventional pacemaker indication

PATH CHF


4 weeks

4 weeks

One Year

4 weeks

Acute Testing at Implant

Randomization Prior to Discharge

Pre-OP Evaluation

Best Unichamber Biventricular

No Pace No Pace

Biventricular Best Unichamber

Best Chronic Pacing Mode

FlexStim

PATH CHF:Study Design PATH CHF


MUSTIC Inclusion Criteria (67 pts)

• Dilated cardiomyopathy of any etiology• NYHA Class III • Optimal individual drug therapy • LBBB and QRS duration >150 msec • LVEF<35% and LVEDD>60mm• 6-MWT<450m• SR & no conventional pacemaker indication


Results Active pacing

Inactivepacing

p

6-min w (m) 399 ± 100 326 ± 134 .0001

QOL score 29.6 ± 21.3

43.2 ± 22.8

.0002

VO2 (ml/min/Kg) 16.2 ± 4.7 15 ± 4.9 0.02

S.Cazeau et al NEJM 2001;344:873-80S.Cazeau et al NEJM 2001;344:873-80

Cardiac Resynchronization Cardiac Resynchronization TherapyTherapyMUSTIC Results (67 pts)

Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk10

15

20

25

30

35

40

*

* †

*

*

*

†

†

Mitr

al r

egur

gita

tion

(%)

MR area

Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk

100

125

150

175

200

225

**

*

*

†

* *

*

†

Left

ven

tric

ular

vol

ume

(mL) *

LVESV and LVEDV

LV Reverse Remodeling

Pacing No pacing

N = 25

Cardiac Resynchronization Cardiac Resynchronization TherapyTherapyMUSTIC Results (67 pts)

MIRACLE Inclusion Criteria (571 pts)

• Moderate or severe HF (NYHA III-IV)• Stable optimal HF medical therapy regimen for

>1mo Diuretics (93-94%) ACE-I or ARB (90-93%) if tollerated β-blocker (55-62%) at stable regimen for>3 months

• QRS duration ≥150 msec • LVEF ≤35% or LVEDD ≥55mm (echo measure)• Sinus rate > 55 bpm • 6 MWT <450m


Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346:1845-1853

Change in MR Jet AreaChange in MR Jet Area

-4-4

-3-3

-2-2

-1-1

00

11

ControlControl(n=118)(n=118)

CRTCRT(n=116)(n=116)

cmcm22

P<0.001P<0.001 P=0.009P=0.009

Change in LVEDDChange in LVEDD

-6-6

-4-4

-2-2

00

22



mmmm P<0.001P<0.001

Absolute Change in LVEFAbsolute Change in LVEF

-2-2

00

22

44

66

88



%%

Baseline (mm)Baseline (mm)69 ± 10

70 ± 10

Baseline (cmBaseline (cm2)7.2 ± 4.9

7.6 ± 6.4Baseline (%)Baseline (%)

22 ± 6

22 ± 6

Paired median change from baseline at 6 months

Cardiac Function and Structure

Cardiac Resynchronization Cardiac Resynchronization TherapyTherapyMIRACLE

Improvement in Peak VOImprovement in Peak VO22

-0.5-0.5

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0



ml/kg

/min

ml/kg

/min

P=0.009P=0.009

Improvement in Improvement in Total Exercise TimeTotal Exercise Time

00

3030

6060

9090

120120



seco

nds

seco

nds

P=0.001P=0.001

Baseline Baseline

(ml/kg/min)(ml/kg/min)

13.7 ± 3.8

14.0 ± 3.5

BaselineBaseline

(secondsseconds)

462 ± 217

484 ± 209

Metabolic Exercise


Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346:1845-1853

VO

2 (

ml/m

in/m

VO

2 (

ml/m

in/m

22))

DODO22 (ml/min/m (ml/min/m22))


OO22ERER

Critical DOCritical DO2 2

DISOXIADISOXIA

Critical VOCritical VO22

VOVO22 = = DODO2 2 X X OO22ERER

NormalNormal

Myocardial Oxidative Metabolism

Control 225 214 204 197 191 179 70

CRT 228 218 213 209 204 201 99

Patients At RiskPatients At Risk

70%70%

75%75%

80%80%

85%85%

90%90%

95%95%

100%100%

00 11 22 33 44 55 66

Months After RandomizationMonths After Randomization

Eve

nt F

ree

Eve

nt F

ree

Sur

viva

lS

urvi

val (

%)

(%

)

CRTCRT

ControlControlP = 0.033P = 0.033Relative risk = 0.60; Relative risk = 0.60; 95% CI (0.37, 0.96)95% CI (0.37, 0.96)

Time to Death or Worsening HF requiring Hospitalization


Survival

80%

85%

90%

95%

100%

0 1 2 3 4 5 6

Months Since Randomization

% o

f P

atie

nts

Su

rviv

ing

Control n=402 CRT n=415

P=0.42

W.T. Abraham for MIRACLE and MIRACLE ICD Investigators


MIRACLE and MIRACLE ICD Trials

QOL & Functional Capacity 6 Months in Moderate to Severe HF

- 20

- 15

- 10

- 5

0

P<0.001 P=0.02 P=0.017P<0.001

QoL Score(MLWHF)

Avg. Change

0%20%40%60%80%

MIRACLE MUSTIC SR MIRACLE ICD Contak CD

P<0.001 P=0.006P=0.007

Data sources:MIRACLE: Circulation 2003;107:1985-90 MUSTIC SR: NEJM 2001;344:873-80MIRACLE ICD:JAMA 2003;289:2685-94 Contak CD: JACC 2003;2003;42:1454-59

Control CRT

NYHA ClassProportion

Changing 1 or more Classes

Improve.

Not Reported


Exercise Capacity 6 Months in Moderate to Severe HF

-20

0

20

40

60 P<0.001 P=0.36 P=0.029

P<0.001

6 Min WalkAvg. Change

(m)

000

1

2

3

MIRACLE MUSTIC SR MIRACLE ICD Contak CD

P<0.001

P=0.029

P=0.04P=0.003

Data sources:MIRACLE: Circulation 2003;107:1985-90 MUSTIC SR: NEJM 2001;344:873-80MIRACLE ICD:JAMA 2003;289:2685-94 Contak CD: JACC 2003;2003;42:1454-59

Control CRT

Peak VO2

Avg. Change (mL/kg/min)


Mortality/Morbidity from Published Randomized, Controlled Trials Risk reduction with CRT

Study (n random.) FU

Mor-tality & Hosp.

Mortal. & HF Hosp.

Mor-tality

HF Mort.

HF Hosp.

MIRACLE (n=453) 6 Mo NR 39%* 27% NR 50%*

MIRACLE ICD (n=369) 6 Mo 2% 0% 0% NR NR

Contak CD (n=490) 3-6 Mo NR NR 30% NR 18%

Meta-analysis (n=1634) 3-6 Mo NR NR 23% 51%* 29%*

* P < 0.05


Effects on Cardiac Function and Oxidative Stress

0,14

0,16

0,18

0,20

0,22

0,24

500 600 700 800 900

dP/ dtmax (mm/ Hg/ s)

MVO

2/H

R (R

elat

ive

Uni

ts) Dobutamin

LV Pacing

P<0.05

Nelson et al. Circulation 2000

Myocardial Oxidative

Metabolism

0

0,02

0,04

0,06

LV RV

k mon

o(m

in-1)

p=0.86

p=0.62

n=8

Myocardial Efficiency

Work Metabolic Index

0

2

4

6

8

10

12

mm

HG

·L·m

-2

Baseline CRT

p =0.024

Ukkonen et al. Circulation 2003

n=7


CRT Does Not Promote Ventricular Arrhythmias

• Analyzed 1,044 patients with ICDs from 2 trials:– CONTAK CD– MIRACLE ICD

• Odds ratio (CI):0.92 (0.67 – 1.27)

Patients with VT or

VF during Follow-up

17,2%18,4%

No CRT CRT

Prop

orti

on

Bradley DJ, et al. JAMA 2003


Baseline ex CPX

ImplantAttempt

SuccessfulImplant

ControlICD

CRTCRT + ICD

Pre-dischargeRandomization

6 Month Follow-up

6 Month Follow-up

CRT

DoubleBlinded

StableMedicalTherapy

1week

•Class NYHA II

•Intent to treat analyses

•Comparison between groups

•Core labs: metabolic exercise, echocardiography, and neurohormone data

CRT

Long term follow up every 6 months

CPX

Cardiac Resynchronization Cardiac Resynchronization TherapyTherapyMIRACLE ICD II

210 Class II 429 Class III/IV

98 Completed 6M FU 82 Completed 6M FU

2 Death 2

1 Missed 6M FU 1

101 Control (ICD+OPT) 85 CRT (CRT+ICD+OPT)

639 Enrolled and Implant Attempted

19 Unsuccessful 191 (91%) Successful

186 Randomized

5 not randomized- 1 death- 4 LV lead dislodge.


Left Ventricular End Systolic Diameter

200

250

300

350

400cm3

Base 6 Mo

P=0.01

Reverse Remodeling in Class II CHF

Left Ventricular End Diastolic Diameter

200

250

300

350

400cm3

Base 6 Mo

P=0.04

Left Ventricular Ejection Fraction

20

22

24

26

28

30%

Base 6 Mo

P=0.02

Control (n=85) CRT (n=69)


Cardiac Resynchronization Cardiac Resynchronization TherapyTherapyRelated Risks

Complications (1)

4,8

3,7

1,5

1,0

1,8

0,3

10,6

10,0

2,3

2,4

1,7

0,3

0 5 10 15

Unsucess. I mplant

LV Lead

Coronary Sinus

I nfection

30 day mortality

Procedure death

Percent of Patients

MI RACLE+CONTAKCD+MI RACLE I CD

I nSync I I I / Attain4193

Reduced Procedure Time with Increased Experience (2)

60

120

180

240

300

Up to first5

Next 6 to10

Next 11more

Center-based experienceIm

pla

nt Tim

e (

min

ute

s) P < 0.001

Study Period AttemptsPrimary LV Lead

MIRACLE 11/98 – 12/00 591 Attain 2187

Contak CD 2/98 – 12/00 517 EasyTrak

MIRACLE ICD 10/99 – 8/01 636 Attain 4189

InSync III 11/00 – 6/02 334 Attain 4193

1. Greenberg, et al. PACE 2003;26(4p2): 952 (Abstract 93)

2. Unpublished data. Medtronic. Inc.

Cumulative Enrollment in Cumulative Enrollment in C.R.T. Randomized TrialsC.R.T. Randomized Trials

0

1000

2000

3000

4000

1999 2001 2003 2005

Results Presented

Cum

ulat

ive

Pat

ient

s

PATH CHF

MUSTI C SR

MUSTI C AFMI RACLE

CONTAK CD

MI RACLE I CD

PATH CHF I I

COMPANI ON

MI RACLE I CD I I

CARE HF

• • Actual Projected�Actual Projected�DOUG SMITHDOUG SMITH


0

5000

10000

15000

Baseline Post-implant

Intensive care

Cardiology

Others

Patient Cost Baseline: 12,784 Euro Patient Cost (Implant included): 12,362 EuroPatient Cost Post-implant: 1,680 Euro

Hospital costs per patient

Cost EffectivenessAnalysis of Biventricular Pacing in HF

Curnis A 2001


Relative Cost of CRTCost per patient

$0$20$40$60

CRT+ICD

CRT

Hip/ knee replace

PTCA

CABG

Dialysis

$ thousands

Total Annual Expenditures

$0 $5 $10 $15 $20

$ BillionsDoug Smith:

Doug Smith:


Weight of Evidence: CRT• More than 4000 patients evaluated in

randomized controlled trials

• Consistent improvement in QOL, functional status, and exercise capacity

• Strong evidence for reverse remodeling– ↓ LV volumes and dimensions LV ejection fraction– ↓ Mitral regurgitation

Courtesy of Dr. Bill Abraham


Reduced Mortality in Heart Failure

ACE-I & Beta Blockade

Reduce Mortality

11,5%

15,6%

12,4%

7,8%

0%4%8%

12%16%

SOLVD-T MERI T-HF

+ CI BI S I I

1 Yea

r M

orta

lity

Placebo Treatment

Further Reduction with CRT + ICD

for Higher Risk Patients

CHFMortality

SuddenCardiac Death

CRT

ICD



• CRT in NYHA class II ? • Which implication in pts with unstable Haemodinamic profile ? • CRT in chronic Atrial Fibrillation ?

• CRT in Right Bundle Branch Block ?

• QRS<120ms or QTc dispersion ?

• “Up-grading” in RVA pacing ?

Actual Key QuestionsActual Key Questions

Creating Realistic patients expectations


• Approximately two-third of patients should experience improvement (responders vs. non-responders)1

• Some patients may not experience immediate improvement

• Have patients set their own goals of what they would like to do following CRT: Grocery shopping, Decreasing Lasix dose Walking to the mailbox without stopping, Lying flat to sleep

• Encourage them to be part of the group that responds to their therapy


Creating Realistic patients expectations

Download - 2005 roma, convegno regionale, la terapia di resincronizzazione cardiaca nello scompenso cardiaco

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